{"title":"Comparing the Benefits and Drawbacks of Stem Cell Therapy Based on the Cell Origin or Manipulation Process: Addressing Immunogenicity.","authors":"Sung-Ho Chang, Chung Gyu Park","doi":"10.4110/in.2023.23.e44","DOIUrl":null,"url":null,"abstract":"<p><p>Mesenchymal stem cells (MSCs) are effective in treating autoimmune diseases and managing various conditions, such as engraftment of allogeneic islets. Additionally, autologous and HLA-matched allogeneic MSCs can aid in the engraftment of human allogeneic kidneys with or without low doses of tacrolimus, respectively. However, HLA alloantigens are problematic because cell therapy uses more HLA-mismatched allogeneic cells than autologous for convenience and standardization. In particular, HLA-mismatched MSCs showed increased Ag-specific T/B cells and reduced viability faster than HLA-matched MSCs. In CRISPR/Cas9-based cell therapy, Cas9 induce T cell activation in the recipient's immune system. Interestingly, despite their immunogenicity being limited to the cells with foreign Ags, the accumulation of HLA alloantigen-sensitized T/B cells may lead to allograft rejection, suggesting that alloantigens may have a greater scope of adverse effects than foreign Ags. To avoid alloantigen recognition, the β2-microglobulin knockout (B2MKO) system, eliminating class-I MHC, was able to avoid rejection by alloreactive CD8 T cells compared to controls. Moreover, universal donor cells in which both B2M and Class II MHC transactivator (<i>CIITA</i>) were knocked out was more effective in avoiding immune rejection than single KO. However, B2MKO and <i>CIITA</i> KO system remain to be controlled and validated for adverse effects such as the development of tumorigenicity due to deficient Ag recognition by CD8 T and CD4 T cells, respectively. Overall, better HLA-matching or depletion of HLA alloantigens prior to cell therapy can reduce repetitive transplantation through the long-term survival of allogeneic cell therapy, which may be especially important for patients seeking allogeneic transplantation.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10767552/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immune Network","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4110/in.2023.23.e44","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/12/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Mesenchymal stem cells (MSCs) are effective in treating autoimmune diseases and managing various conditions, such as engraftment of allogeneic islets. Additionally, autologous and HLA-matched allogeneic MSCs can aid in the engraftment of human allogeneic kidneys with or without low doses of tacrolimus, respectively. However, HLA alloantigens are problematic because cell therapy uses more HLA-mismatched allogeneic cells than autologous for convenience and standardization. In particular, HLA-mismatched MSCs showed increased Ag-specific T/B cells and reduced viability faster than HLA-matched MSCs. In CRISPR/Cas9-based cell therapy, Cas9 induce T cell activation in the recipient's immune system. Interestingly, despite their immunogenicity being limited to the cells with foreign Ags, the accumulation of HLA alloantigen-sensitized T/B cells may lead to allograft rejection, suggesting that alloantigens may have a greater scope of adverse effects than foreign Ags. To avoid alloantigen recognition, the β2-microglobulin knockout (B2MKO) system, eliminating class-I MHC, was able to avoid rejection by alloreactive CD8 T cells compared to controls. Moreover, universal donor cells in which both B2M and Class II MHC transactivator (CIITA) were knocked out was more effective in avoiding immune rejection than single KO. However, B2MKO and CIITA KO system remain to be controlled and validated for adverse effects such as the development of tumorigenicity due to deficient Ag recognition by CD8 T and CD4 T cells, respectively. Overall, better HLA-matching or depletion of HLA alloantigens prior to cell therapy can reduce repetitive transplantation through the long-term survival of allogeneic cell therapy, which may be especially important for patients seeking allogeneic transplantation.
间充质干细胞(MSCs)可有效治疗自身免疫性疾病和控制各种病症,如异体胰岛移植。此外,自体间充质干细胞和HLA匹配的异体间充质干细胞可分别在使用或不使用低剂量他克莫司的情况下帮助人类异体肾脏的移植。然而,HLA 同种抗原是个问题,因为细胞疗法为了方便和标准化,使用的 HLA 不匹配异体细胞多于自体细胞。特别是,HLA不匹配的间充质干细胞比HLA匹配的间充质干细胞显示出更多的Ag特异性T/B细胞和更快的活力下降。在基于CRISPR/Cas9的细胞疗法中,Cas9能诱导受体免疫系统中的T细胞活化。有趣的是,尽管其免疫原性仅限于具有外来抗原的细胞,但HLA同种抗原致敏的T/B细胞的积累可能会导致异体移植排斥反应,这表明同种抗原可能比外来抗原具有更大的不良影响范围。为了避免同种抗原识别,β2-微球蛋白基因敲除(B2MKO)系统消除了I类MHC,与对照组相比,能避免异体反应性CD8 T细胞的排斥反应。此外,同时敲除 B2M 和 II 类 MHC 转座子(CIITA)的通用供体细胞比单一敲除更能有效避免免疫排斥反应。然而,B2MKO 和 CIITA KO 系统仍有待控制和验证其不良影响,如由于 CD8 T 细胞和 CD4 T 细胞对 Ag 的识别能力不足而分别导致肿瘤的发生。总之,在细胞治疗前进行更好的HLA配型或清除HLA同种抗原可通过异体细胞治疗的长期存活减少重复移植,这对寻求异体细胞移植的患者尤为重要。
期刊介绍:
Immune Network publishes novel findings in basic and clinical immunology and aims to provide a medium through which researchers in various fields of immunology can share and connect. The journal focuses on advances and insights into the regulation of the immune system and the immunological mechanisms of various diseases. Research that provides integrated insights into translational immunology is given preference for publication. All submissions are evaluated based on originality, quality, clarity, and brevity